Implantable Medical Devices: Biofilms and Infections

Posted on Feb 22, 2025 in Biology

Implantable Medical Devices

Implantable devices repair or replace structure or function that is defective or lost due to congenital imperfection, trauma, surgery, or disease. They are also used for local drug delivery. Devices are made of biomaterials, which must be biocompatible with host tissues. Biomaterials are preferable to tissues or organs from animal sources due to reduced risk of rejection and disease transmission. Examples include silicone elastomer, polyurethanes, Teflon®, Dacron®, titanium, stainless steel, and ceramics.

However, there is a risk of biodegradation, mechanical malfunction, or infection.

Categories of Indwelling Devices

  • Totally implanted: Hip, knee, and other joint prostheses, hydrocephalus shunts, prosthetic heart valves, pacemakers, vascular grafts, intraocular lenses.
  • Partially-implanted: Central venous catheters (CVC), continuous ambulatory peritoneal dialysis (CAPD), external ventricular drains.
  • Non-surgically implanted: Urinary catheters, voice prostheses.

Physiological Activity in Biofilms

Heterogeneity:

  • Biofilms are composed of many microbial species with nutritional interactions.
  • Chemical microenvironments within microcolonies show spatial and temporal chemical variation.
  • Microzones are beneficial to different communities.

Important Features of Biofilms:

  • General tolerance of treatment with biocides, antimicrobial agents, and disinfectants.
  • Evasion of host immune responses.

Contributing Factors to Recalcitrance:

  • Physical protective properties of the extracellular matrix.
  • Physiological state of cells within the biofilm.
  • Nutrient-limitation, leading to slow growth or no growth.
  • “Biofilm phenotype.”

Mechanisms of Biofilm Tolerance

(1) Inability of the agent to penetrate fully:

Extent of antibiotic penetration is influenced by:

  • Chemical nature of the compound and binding capacity of the polymeric matrix.
  • Levels of the agent.
  • Distribution of biomass within the biofilm and its turnover.
  • Local hydrodynamic effects.
  • Microbial enzyme activity.

Category 1 Device Infection

Most are caused by:

  • Staphylococcus epidermidis and other coagulase-negative (CoN) staphylococci, S. aureus, and coryneforms; Cutibacterium acnes (formerly Propionibacterium acnes).
  • “Late” infection – bacteria from respiratory, alimentary, or genitourinary tracts, e.g., Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, and Enterococcus spp.

Fungal Prosthetic Joint Infection:

  • Candida albicans, Aspergillus spp.

Heart Valve Infection:

  • 2. 9%; C. albicans and other Candida spp.

Joint Prosthesis Infection:

  • 1-3%; C. albicans most common.

Category 2 Device Infection

Organisms may be introduced during the use of the device. Skin microorganisms can reach the bloodstream via the outer surface of the device or via administered IV fluids. Intravascular catheters are in place for weeks or months and are used at least twice a day; the period of risk is constant.

Microorganisms from different sources:

  • Enteric – E. coli
  • Environmental – Pseudomonas aeruginosa, Candida albicans
  • Skin microbiota

Category 3 Devices

Often involve complex communities of microorganisms.

Voice Prostheses:

  • Constant period of risk.
  • Interference with function (especially Candida spp.).

Indwelling Urinary Catheters:

  • Colonized by Gram-positive and Gram-negative bacteria (enteric or environmental).

Leaving the Biofilm

  • Desorption: Early surface colonizers leave (attachment reversal).
  • Detachment: External forces are involved (abrasion, erosion, sloughing, grazing).
  • Dispersion: Active phenotypic switch.

Dispersion from the Biofilm

  • A result of responding to environmental (external) cues or internal (native) cues and producing a release factor.
  • Induced, external dispersion may result in the majority of the biofilm being removed.
  • Native dispersion involves only parts of the biofilm being removed.
  • c-di-GMP is involved in dispersion.

Cell-to-Cell Signaling: Quorum Sensing (QS)

  • Most bacteria exhibit multicellular behavior.
  • Individual cells communicate with neighboring cells by means of chemical signal molecules.
  • The cell population can mount a unified response.
  • Ultimately enhances survival capacity.

Quorum Sensing and Formation of Mature Biofilms

  • Biofilm is an “organized”, differentiated state.

The “Foreign Body Response” to Biomaterials

The body coats foreign implants with a film (e.g., fibronectin, collagen), which may serve as receptors for colonizing microorganisms. The presence of a foreign body may reduce host defenses, e.g., phagocytic and bactericidal capacity of polymorphonuclear leukocytes (PMNL) and cellular immunity.

Small Colony Variants (SCVs) and Device-Related Infection

  • SCVs are bacterial phenotypic variants that reproduce at a very slow rate.
  • Almost all metabolic functions are decreased; membrane proton motive force (pmf) is greatly decreased.
  • Reduce the expression of virulence factors.
  • Staphylococcal SCVs survive in phagocytic cells.
  • Are SCVs an adaptation for chronic infection where biofilm growth is important?

Urinary Catheters

Sources of Infecting Organisms:

  • Introduced into the urethra or bladder as the catheter is inserted.
  • Can travel intraluminally or extraluminally.
  • Initial colonizers: single species, e.g., E. coli or Proteus mirabilis.
  • Mixed communities develop, including P. aeruginosa, K. pneumoniae.

Urinary Catheter Encrustation

Some organisms (e.g., P. mirabilis) alter local pH. Urease hydrolyzes urea, and the pH is raised. Precipitation of minerals, e.g., calcium phosphate (hydroxyapatite) and magnesium ammonium phosphate (struvite), is deposited in catheter biofilms.

Biofilm Structure

Architecture varies but is commonly:

  • Highly hydrated.
  • Significant proportions of polymeric material.

Biofilms observed in laminar flow environments:

  • Microcolonies: “mushroom-shaped” structures, stacks, towers, “streamers.”
  • Channels and pores.

Biofilm Matrix

  • Polysaccharide, proteins, nucleic acids, and other components from the environment; highly hydrated.
  • Extracellular polymeric substances (EPS) play an integral role.
  • Variation in chemical composition leads to variation in physical properties.

Strategies Using Antimicrobials

  • Broad-spectrum antibiotic prophylaxis immediately preoperatively.
  • Antibiotic powder mixed into bone cement, e.g., gentamicin bound to polymethyl methacrylate (PMMA).
  • Coat or impregnate the catheter with antibiotics or with antiseptics.

Antiseptic-Coated or Impregnated Catheters

For example:

  • Chlorhexidine- or iodine-complexed polymers.
  • Polyurethane CVC coated with metallic silver.

Is widespread emergence of antiseptic-resistant microorganisms less likely to occur than for antibiotics? Data and evidence are unclear at the moment.

Intraluminal Antibiotic Locks

(Antibiotic lock technique)

  • High concentrations of antibiotic solution or other antimicrobial locked into the catheter lumen, e.g., for 2-12 hours every day for two weeks.

Example: Allon (2007) CJASN 2(4), 786-800. In patients with catheter-related bacteremia. The final antibiotic concentration in the lock is approximately 100-fold higher than the therapeutic plasma antibiotic concentration. The antibiotic-heparin lock solution is instilled into each catheter port at the end of the dialysis session and aspirated before the next dialysis session.

What is a Biofilm?

  • “Structured community of microbial cells enclosed in a self-produced polymeric matrix and adherent to an inert or living surface” (Costerton et al., 1999).

Not just planktonic cells settled on a surface?

  • Adhesion to the substratum is complex.
  • Biofilm architecture is complex and dependent upon several factors.
  • Dynamic environments; cells detach and colonize other surfaces.

Why Do Cells Attach to a Surface?

  • Biological response to environmental cues?
  • Contact with a surface, and “touch” initiates a biological response?
  • Cyclic-di-GMP (c-di-GMP) – an intracellular second messenger – is involved in transitions from planktonic to biofilm and biofilm to planktonic lifestyles.

Factors Affecting Attachment

  • Fimbriae or pili may span the cell-solid surface distance.
  • Fibrils, capsule, LPS, extracellular polysaccharide, lipoteichoic acid, cell surface proteins, and eDNA can mediate adhesion.
  • Host-bacterium interaction: specific bacterial surface proteins may interact with host receptors.
  • Chemical composition of the surface.
  • Physical nature of the surface, affecting its form, waviness, and roughness.

Impact of Surface Topography on Single-Cell Adhesion

Bacterial adhesion is favored on recessed portions of a micropatterned surface, and bacteria tend to attach preferentially to patterns in the micrometer range rather than to smooth surfaces.

Factors Affecting Attachment in Liquid Medium

  • Availability of metabolites.
  • “Conditioning film.”
  • Microorganisms tend not to adhere to nutrient-free surfaces.

What Does a Biofilm Look Like?

  • Confocal laser scanning microscopy (CLSM):
    • Imaging without dehydration.
    • Reveals the complex nature of biofilm architecture.
    • Discrete matrix-enclosed microcolonies.
  • Biofilm structure depends upon location, microorganisms, and nutrient availability.

Mechanisms of Biofilm Tolerance

Reaction-Diffusion Limitation Model

  • Strongly charged or chemically highly reactive agents are quenched within the matrix during diffusion.
  • EPS and cellular materials (from dead cells) in peripheral regions of the (treated) biofilm may act as substrates for chemically reactive biocides.
  • May neutralize the treatment agent, leading to even less availability and diffusion across the biofilm.

Enzyme-Mediated Inactivation

  • β-lactamase enzymes are upregulated in biofilms.
  • Catalase.

Cell Physiology: Nutrient Status and Growth Rate

Susceptibility of bacterial cells towards antimicrobials is affected by:

  • Nutrient status.
  • Growth rate.
  • Temperature.
  • pH.
  • Previous exposure to sub-effective concentrations.
  • Oxygen status.

Physiological factors change with bacterial cell growth rate:

  • e.g. proteases, siderophores, EPS, OMPs, phospholipids.

Mechanisms of Biofilm Tolerance

Starvation Response:

  • Nutrient limitation leads to a stringent response (involving relA and spoT genes).
  • Nguyen et al. (2011): stringent response in P. aeruginosa biofilms is responsible for increased tolerance to antibiotics.

General Stress Response:

  • Specific gene expression is induced on entry into stationary phase and/or under other conditions of stress (involving RpoS, which interacts with RNA polymerase).
  • Has a large impact on the cell’s physiology under suboptimal conditions.

Is There a Distinct “Biofilm Phenotype”?

  • Biologically programmed response to growth on a surface?
  • Are there biofilm-specific patterns of gene expression?
  • Or is there just a series of events where the cells adapt to the environment?

Mechanisms of Biofilm Tolerance/Resistance

As with planktonic cells, antimicrobial failure is also due to:

  • Inherent insusceptibility.
  • Acquisition of resistance.
  • Emergence of unexpressed phenotypes.
  • Inactivation of antibiotics.

Chances of acquired resistance increased?

  • Exchange of DNA and promotion of genetic diversity within biofilm; genotypic differences.

Persisters

  • Sub-population of tolerant cells.
  • e.g. P. aeruginosa biofilm and planktonic cells have similar antimicrobial susceptibility (Spoering & Lewis, 2001).
  • Most biofilm cells are eradicated by agents, but a small fraction of persisters are invulnerable.
  • Biofilm populations are enriched with persisters (biofilm-specific phenotype).

Summary: Resistance of Biofilm Cells to Antimicrobial Agents is Multifactorial

  • Limited diffusion of the agent.
  • Neutralization of the agent.
  • Cellular growth rate differences.
  • Nutrient-limited phenotypes.
  • “Biofilm phenotype.”
  • General stress response and stringent response.
  • Inherently resistant cells.
  • Cells with acquired resistance or with previous exposure to sub-inhibitory concentrations.
  • Persisters.